Is APOB p.Arg214Cys (c.640C>T) pathogenic?

APOB p.Arg214Cys (c.640C>T) is classified Conflicting classifications of pathogenicity in APOB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-05-24). AlphaMissense: likely benign (0.1354); Very rare (popmax 0.00333%, amr); Associated with familial hypobetalipoproteinemia 1.

What condition is associated with APOB p.Arg214Cys (c.640C>T)?

APOB p.Arg214Cys (c.640C>T) is associated with familial hypobetalipoproteinemia 1, hypercholesterolemia, autosomal dominant, type B (ClinVar).

How common is APOB p.Arg214Cys (c.640C>T) in the general population?

APOB p.Arg214Cys (c.640C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about APOB p.Arg214Cys (c.640C>T)?

AlphaMissense predicts likely benign (score 0.1354) — an in-silico prediction, not a clinical call.

APOB p.Arg214Cys

c.640C>T · rs763352655 · VCV1753371

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1354 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

familial hypobetalipoproteinemia 1

Computational evidence

Protein change
AlphaMissense	0.1354	likely benign
REVEL	0.102	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.073	GERP -3
Regional constraint	o/e 1.00	unconstrained · MANE · 32 kb · p 0.91 · regional, not allelic
Overall
CADD	16.86	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,000 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00062% 10/1,614,098 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,000
African / African-American	0.00267%	37,469
European (non-Finnish)	0.000508%	196,675

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: APOB
Protein: p.Arg214Cys
Coding: c.640C>T
MANE Select: NM_000384
dbSNP: rs763352655
Type: single nucleotide variant
Location: chr2:21037153 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Residue 214: the vitellogenin domain

Full APOB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial hypobetalipoproteinemia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypercholesterolemia, autosomal dominant, type B

Similar variants

APOB p.Arg214His Benign/Likely benign ★★ same residue
APOB p.Arg214Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
APOB p.Arg214Ser Uncertain significance ★ ⚠ same residue
APOB c.1830-1G>A Pathogenic ★★ same condition
APOB c.2604+1G>A Likely pathogenic ★★ same condition
APOB c.537+1G>T Pathogenic/Likely pathogenic ★★ same condition
APOB p.Arg1333Ter Pathogenic ★★ same condition
APOB p.Arg2012Ter Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/apob-p-arg214cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown